Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury

Acute lung injury (ALI) is associated with overproduction of inflammatory mediators in lung tissue. Previous studies have revealed that inflammation induces activation of phosphodiesterase 4B (PDE4B) accompanied by the production of inflammatory mediators, but the detailed mechanism remains unclear. Here, we focused on the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome complexes to study the crosstalk between PDE4B and NF-E2-related factor 2 (Nrf2). We used global knockout PDE4B or Nrf2 mice to prepare LPS induced acute lung injury model by intratracheally administration, and LPS primed bone marrow-derived macrophages (BMDMs), following overexpression of PDE4B or Nrf2, luciferase activity analysis, and chIP-qPCR analyses. We found that deficiency of PDE4B could potently attenuate the lung histopathological changes, suppress the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-18, and cleaved caspase-1, 8, and GSDMD accompanied with defective activation of the ROS/Nrf2/NLRP3. Meanwhile deficiency of Nrf2 showed the similar results. Furtherly, overexpression by PDE4B or Nrf2 plasmid transfection in MH-S cells could enhance the Nrf2 or PDE4B expression. Luciferase analysis suggested that Nrf2 activated PDE4B promoter activity, while PDE4B could increase Nrf2 substrate ARE activity in MH-S cells in dose dependent manners. ChIP-qPCR analyses showed that Nrf2 bound to the PDE4B promoter region at ̴ 1532 to ̴1199 position in macrophages. Altogether, deficiency of PDE4B inhibit the inflammasome activation and pyroptosis in LPS stimulated lung injury model and macrophages by regulating ROS/Nrf2/NLRP3 activation. The study provides new insight that PDE4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2. LPS-induces ALI by activating oxidative stress and NLRP3 inflammasome. Accumulated ROS showed a positive effect to Nrf2 and NLRP3 activation in lung injury. LPS is also enhanced PDE4B expression. Activated Nrf2 binds with PDE4B promotor leading to generate inflammatory cytokines in macrophages. Thus, deletion of PDE4B might be a promising target for the treatment of Nrf2/NLRP3 inflammasome-related inflammatory diseases. [Display omitted] •PDE4B deficiency is essential to regulate ROS/Nrf2/NLRP3 pathway and pyroptosis.•PDE4B deficiency shows defective activation of Nrf2.•Positive feedback between Nrf2 and PDE4B in macrophages during inflammation process.•Nrf